Method of preparing delta-pregnenes



Patented Jan. 12, 1954 UNITED STATES PATENT OFFICE METHOD OF PREPARING ALPREGNENES Seymour Bernstein and Rose Mary Antonucci, Pearl River, and Milton D. Heller, Monsey, N. Y., assig nors to American Cyanamid Com pany, New York, N. Y., a corporation of. Maine No Drawin Application December 4, 1951,- Serial No. 259,903

4 Claims. (01. .260--397.4l 1 This invention relates to a new method for the preparation of M-pregnenes. More particularly, it relates to a method for the preparation of n -pregnene-11B,1'7a,21-triol-3,20-dionei Recently interest in the steroid field has been 5 greatly stimulated by the discovery that cortisone can be used not only in the treatment of rheumatic diseases but in the treatment of a wide variety of pathological conditions. The compound cortisone which occurs naturally in the adrenal cortex is also known as Kendalls Com pound E. cortisone may be described chemically as n -pregnene-17a,21-diol-3,11,20-trione. A compound structurally related to cortisone has also been described by Kendall and others and has been given the name Kendalls Compound 1 11 011 F. Compound F differs from cortisone in hav- 0 ing a hydroxyl radical in place of a keto group in the ll-position. Published results on the activi:

ity of Compound F have been somewhat meager in the literature primarily because of the very limited amounts of Compound F available for clinical study. The results thus far reported appear to indicate that Compound F may be more active than cortisone itself. Indeed, reports in the literature have indicated that Compound F, and not cortisone, is the true hormone of the 20112011 0 GHaOH The intermediate used in the above illustrated process can be prepared from cortisone by reactadrenal cortex. It is therefore desirable that a ing cortisone with ethylene glycol and subsernethod be available which is capable of producquently th it i l i hydride i ing Compound F in good yields. solvent. These products and their method of Compound has the following Structural preparation are described and claimed in our formula: copending application, Serial No. 259,902, filed December 4, 1951, now Patent No. 2,622,081, issued onion December 16, 1952. I O The process of the present invention is carried imOE out in a solvent in the presence of a mineral acid Q and water. The solvent may be an alcohol such as methyl, ethyl, propyl, butyl or amyl alcohol, CH3 dioxane or a ketone such as acetone, methyl ethyl 4o ketone and the like.

The process is usually carried out at a temperature within the range of 20 C. to about 150" C. It is preferable to carry out the reaction at the refluxing temperature of the particular We have found that this compound can be solvent used. At these temperatures the reacprepared in good yields from M-pregnenetion is usually complete in a matter of 15 minutes 11B,17a,21-triol-3,20-dione di-ethylene keta-l. The to about 2 hours. However, the reaction may be reaction to prepare the compound of the present made to take place at room temperature by al invention may be illustrated by the following lowing the reaction mixture to stand at room equation: temperature for a period up to 24 hours.

In carrying out the reaction it is also necessary to have present a mineral acid which acts as a catalyst. The preferred mineral acid for the present process is sulfuric acid, although, if desired, other acids such as hydrochloric, hydrobromic, etc., can be used.

The product is recovered from the reaction mixture by neutralizing the reaction mixture with mild alkali, such as sodium bicarbonate, and removing the solvent by evaporation under reduced pressure. The residual mixture is then extracted with a solvent such as ethyl acetate, and upon evaporation of the solvent the product is obtained as a crystalline material. The product can be further purified by crystallization from an organic solvent or mixture of organic solvents such as acetone and petroleum-ethen,

The following example illustrates the preparation of A -pregnene-11p,l7,21 diol 3,20 dione (Kendalls Compound F) by the method of the present invention. 7

A mixture of 70 mg. of A -pregnene-1lfi,17a,21-

triol-3,20-dione (ii-ethylene ketal, '7 ml. of ethanol and 0.7 ml. of 8.5% sulfuric acid (v./v.) was refluxed for one and one third hours. The cooled reaction mixture was neutralized with a solution of sodium bicarbonate and was concentrated under reduced pressure for the removal of ethanol. The residual mixture was extracted with ethyl acetate. The residue obtained upon evaporation of the ethyl acetate was crystallized from acetone-petroleum ether (boiling point 64-66 0.), weight 21 mg. The'recrystallizations from acetone-petroleum ether (boiling point 64-66 C.) gave 16 mg. of M-pregnene-llel'l jl-triol- 3,20-dione (Kendalls Compound F), melting point 204-205.5 C., with previous browning,

We claim:

1. A method of preparing the compound having the formula:

CHIOH C O ---0H which comprises reacting A -pregnene-11p,17a,21- triol-3,20-dione diethylene ketal with water in the presence of a solvent and a mineral acid and 17a,21t!iO1-3,20-di0118 which comprises reacting References Cited in the file of this patent UNITED STATES PATENTS Name Date Fernholz Aug. 22, 1944 Number 

1. A METHOD OF PREPARING THE COMPOUND HAVING THE FORMULA: 